US3147258A - Amino chromones with central nervous system stimulating activity - Google Patents
Amino chromones with central nervous system stimulating activity Download PDFInfo
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- US3147258A US3147258A US155468A US15546861A US3147258A US 3147258 A US3147258 A US 3147258A US 155468 A US155468 A US 155468A US 15546861 A US15546861 A US 15546861A US 3147258 A US3147258 A US 3147258A
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- methoxy
- chromone
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- 210000003169 central nervous system Anatomy 0.000 title description 6
- 230000004936 stimulating effect Effects 0.000 title description 6
- VSZPIIMZVZQSKS-UHFFFAOYSA-N 2-aminochromen-4-one Chemical class C1=CC=C2OC(N)=CC(=O)C2=C1 VSZPIIMZVZQSKS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 15
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- -1 AMINO CHROMONES Chemical class 0.000 description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 7
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 5
- 239000002269 analeptic agent Substances 0.000 description 5
- 230000003555 analeptic effect Effects 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 230000029058 respiratory gaseous exchange Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- IUEZUACPJJGGEX-UHFFFAOYSA-N 8-(chloromethyl)-7-methoxy-2,3-dimethylchromen-4-one Chemical compound O1C(C)=C(C)C(=O)C=2C1=C(CCl)C(OC)=CC=2 IUEZUACPJJGGEX-UHFFFAOYSA-N 0.000 description 3
- FKCHROJXIXUTGD-UHFFFAOYSA-N 8-(chloromethyl)-7-methoxy-3-methyl-2-phenylchromen-4-one Chemical compound ClCC=1C(OC)=CC=C(C(C=2C)=O)C=1OC=2C1=CC=CC=C1 FKCHROJXIXUTGD-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000994 depressogenic effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- ORRZGUBHBVWWOP-UHFFFAOYSA-N 4-ethyl-4-methylpiperidine-2,6-dione Chemical compound CCC1(C)CC(=O)NC(=O)C1 ORRZGUBHBVWWOP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 2
- 229960000750 bemegride Drugs 0.000 description 2
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 229940105631 nembutal Drugs 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- INMLBKCDGWTFMQ-UHFFFAOYSA-N 2-ethyl-7-methoxy-3-methyl-8-(morpholin-4-ium-4-ylmethyl)chromen-4-one;chloride Chemical compound [Cl-].COC1=CC=C2C(=O)C(C)=C(CC)OC2=C1C[NH+]1CCOCC1 INMLBKCDGWTFMQ-UHFFFAOYSA-N 0.000 description 1
- HKMYUTZXBNCDAN-UHFFFAOYSA-N 7-methoxy-2,3-dimethyl-8-(morpholin-4-ium-4-ylmethyl)chromen-4-one;chloride Chemical compound [Cl-].COC1=CC=C(C(C(C)=C(C)O2)=O)C2=C1C[NH+]1CCOCC1 HKMYUTZXBNCDAN-UHFFFAOYSA-N 0.000 description 1
- JTSUQDCPLOUMAY-UHFFFAOYSA-N 7-methoxy-3-methyl-2-phenyl-8-(piperidin-1-ylmethyl)chromen-4-one;hydrochloride Chemical compound [Cl-].C1CCCC[NH+]1CC=1C(OC)=CC=C(C(C=2C)=O)C=1OC=2C1=CC=CC=C1 JTSUQDCPLOUMAY-UHFFFAOYSA-N 0.000 description 1
- OQHLMHQKPDQVFI-UHFFFAOYSA-N 8-(chloromethyl)-7-methoxychromen-4-one Chemical class ClCC=1C(=CC=C2C(C=COC=12)=O)OC OQHLMHQKPDQVFI-UHFFFAOYSA-N 0.000 description 1
- RZVNRCJUMHVUEU-UHFFFAOYSA-N 8-(diethylaminomethyl)-2-ethyl-7-methoxy-3-methylchromen-4-one;hydrochloride Chemical compound [Cl-].O1C(CC)=C(C)C(=O)C2=C1C(C[NH+](CC)CC)=C(OC)C=C2 RZVNRCJUMHVUEU-UHFFFAOYSA-N 0.000 description 1
- ZYUBDTCAWJPRNY-UHFFFAOYSA-N 8-(diethylaminomethyl)-7-methoxy-2,3-dimethylchromen-4-one;hydrochloride Chemical compound Cl.O1C(C)=C(C)C(=O)C2=C1C(CN(CC)CC)=C(OC)C=C2 ZYUBDTCAWJPRNY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UDHXJZHVNHGCEC-UHFFFAOYSA-N Chlorophacinone Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)C(=O)C1C(=O)C2=CC=CC=C2C1=O UDHXJZHVNHGCEC-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- RCISIXJGNBXXPZ-UHFFFAOYSA-N Dimefline hydrochloride Chemical compound [Cl-].C[NH+](C)CC=1C(OC)=CC=C(C(C=2C)=O)C=1OC=2C1=CC=CC=C1 RCISIXJGNBXXPZ-UHFFFAOYSA-N 0.000 description 1
- 208000006633 Tonic-Clonic Epilepsy Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Definitions
- Formula 1 0 l ll CHaO 0/R2 (lHzRIIOl wherein R is a member selected from the group consisting of in which R and R are alkyl radicals having less than 3 carbon atoms,
- N H and N H 0 R is a member selected from the group consisting of alkyl radicals having less than 3 carbon atoms or phenyl and R is an alkyl radical having less than 3 carbon atoms.
- the compounds covered by Formula 1 may be prepared by condensing a substituted 8-chloromethyl-7-imethoxy chromone in a solvent with a secondary amine in molar ratio 1:2 under reflux boiling or in an autoclave; cooling and filtering the reaction mixture and concentrating it until dry under vacuum; taking up the residue in Water and extracting the undissolved portion by means of a solvent; working the extract with a saturated solution of sodium chloride, drying it on anhydrous sodium sulphate and admixing it with alcoholic hydrochloric acid in excess; concentrating the extract until dry under vacuum and recrystallizing the residue from a solvent.
- the substituted 8-chloromethyl-7-methoxy chromone may be either 8-chloromethyl-2,3-dia1kyl-7-methoxy chro-rnone or 8-chloromethyl-2-aryl-3-alkyl-7-methoxy chromone.
- secondary amines examples include dimethylamine, diethylamine, piperidine and morpholine.
- EXAMPLE I 8 Dimethylaminomethyl 7 Methoxy 3 Methyl 2- Phenyl Chr0m0ne-HCl A. mixture of 15.7 gr. of 8-chloromethyl-7-methoxy-3- methyl-Z-phenylchromone, 400 ml. of absolute ethanol and 15 ml. of an alcoholic solution of dimethylarnine 10% was heated in an autoclave for 5-8 hrs. at -100 C.
- the yield was 51% and a product was obtained having a melting point of l87-188 C.
- the yield was of 71% and a product was obtained having a melting point of 217-218 C.
- the yield was 72% and a product was obtained having a melting point of 202-204 C.
- EXAMPLE V 8 Dimethylaminamethyl 3 Ethyl 7 Methoxy 2- phenyl Clzromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-3-ethyl-7-methoxy-2-phenyl chromone and dimethylamine in a molar ratio of 1:2.
- the yield was of 31% and a product was obtained having a melting point of 208-209 C.
- the yield was 36% and a product was obtained having a melting point of 205-206 C.
- the yield was 43% and a product was obtained having a melting point of 226-227 C.
- the yield was 21% and a product was obtained having a melting point of -l92 C.
- the yield was 68% and a product was obtained having a melting point of 202-203 C.
- the yield was 66% and a product was obtained having a melting point of 223-224 C.
- the yield was 64% and a product was obtained having a melting point of 224-225" C.
- the yield was 42% and a product was obtained having a melting point of -196 C.
- the yield was 53% and a product was obtained having a melting point of 208-209 C.
- the yield was 44% and a product was obtained having a melting point of 185-186 C.
- the yield was 46% and a product was obtained having a melting point of 214-215 C.
- the yield was 44% and a product was obtained having a melting point of l84185 C.
- the yield was 42% and a product was obtained having a melting point of l77-178 C.
- the analeptic activity of these products was tested to determine whether the DL of Nembutal, injected endoperitoneally into albino mice had an increased effect when treated with a single subcutaneous injection of the drugs under examination.
- the breathing stimulating activity was tested on two compounds only of those illustrated above, namely on the compounds according to Examples XII and I, which are the most active compounds from the analeptic point of view.
- the breathing stimulating activity was tested on nonnarcotized rabbits and on rabbits whose respiration was depressed by means of 10 mg./kg. of morphine.
- the last column gives the analeptic respiratory activity defined as the capacity of the drug in question to restore the morphine depressed breathing above the normal ventilation value.
- the metrazol is not capable of restoring the depressed breathing up to the normal values and therefore bemegride was taken as a standard. 7
- the compounds according to Examples X, XII, I and IX were tested in view of the chronic toxicity by giving them to albino mice growing up (10 males and 10 females) so that, for instance, said animals got pro die ca. A of the DL The treatment was continued for 50 days. The treated animals had, almost all, a weight increase greater than that of the control animals and an increase in red globules. No remarkable statistical differences between the weight averages of the various inner organs were found and no histologic lesions in said organs could be ascertained.
- R is a member selected from the group consisting of cmR-Hcl alkyl having less than 3 carbon atoms and phenyl and herein R 1s a member selected from the group con- R3 is alkyl having less than 3 carbon atoms. slstmg of 2. 8-dimethylaminomethyl 7 methoxy 3 methyl-2- R4 phenyl chromone-HCI. 3. 2,3-dimethyl 8 dimethyl-arninomethyl-7-methoxy- R5 5 chromone-HCI.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent AMINO CHROMONES WHTH CENTRAL NERVOUS SYSTEM STIMULATING ACTlVlTil Paolo Da Re, Milan, Italy, assignor to Recordatt Laboratorio Farmacologico S.p.A., Milan, Italy No Drawing. Filed Nov. 28, 1961, Ser. No. 155,468 Claims priority, application, Switzerland, Oct. 16, 1959, 79,522 4 Claims. (Cl. 260-2473) This invention relates to novel organic compounds possessing central nervous system stimulating activity, and particularly brain stem stimulants. This application is a continuation-in-part of Application Nos. 840,536 and 58,899, filed September 17, 1959, and September 28, 1960, respectively, both now abandoned.
It is an object of the invention to provide improved compounds of the above-noted type.
Compounds according to the invention are represented by the general formula:
Formula 1 0 l ll CHaO 0/R2 (lHzRIIOl wherein R is a member selected from the group consisting of in which R and R are alkyl radicals having less than 3 carbon atoms,
N H and N H 0 R is a member selected from the group consisting of alkyl radicals having less than 3 carbon atoms or phenyl and R is an alkyl radical having less than 3 carbon atoms.
The compounds covered by Formula 1 may be prepared by condensing a substituted 8-chloromethyl-7-imethoxy chromone in a solvent with a secondary amine in molar ratio 1:2 under reflux boiling or in an autoclave; cooling and filtering the reaction mixture and concentrating it until dry under vacuum; taking up the residue in Water and extracting the undissolved portion by means of a solvent; working the extract with a saturated solution of sodium chloride, drying it on anhydrous sodium sulphate and admixing it with alcoholic hydrochloric acid in excess; concentrating the extract until dry under vacuum and recrystallizing the residue from a solvent.
The substituted 8-chloromethyl-7-methoxy chromone may be either 8-chloromethyl-2,3-dia1kyl-7-methoxy chro-rnone or 8-chloromethyl-2-aryl-3-alkyl-7-methoxy chromone.
Examples of secondary amines which may be employed include dimethylamine, diethylamine, piperidine and morpholine.
Compounds coming within the scope of the present invention include:
8-dimethylaminomethyl-7-methoxy-3-methyl-2- phenylchromone-HCl;
8-diethylaminomethyl-7 methoxy-3-methyl-2- phenylchromone-HCI;
7-methoxy-3-methyl-2-phenyl-8-piperidinomethyl chromone-HCl; 7-methoxy-3-methyl-8-morpholinomethyl-2- phenylchromone-HCI; 8-dimethylaminomethyl-3-ethyl-7-methoxy-2- phenylchromone-HCI; 8-diethylarninomethyl-3-ethyl-7-methoxy-2- phenylchromone-HCl; 3-ethyl-7-metl1oxy-2-phenyl-8-piperidinomethylchromone-HCI; 3-ethyl-7-methoxy-8-rnorpholinomethyl-Z-phenylchromone-HCl; 2,3-dimethyl-8-dimethyl-aminomethyl-7-methoxychromone-HCI; 8-diethylaminomethyl-2,3-dimethyl-7-methoxychromone-HCl; 2,3-dimethyl-7-methoxy-8-piperidinomethyl chromone-HCI; 2,3-dimethyl-7-methoxy-8-morpholinomethyl chromone-HCl; 3-ethyl-2-methyl-7-methtoxy-8-piperidinomethyl chrornone-HCI; 3-ethyl-2-methyl-7-methoxy-8-morpholinomethyl chromone-HCI; 8-diethylaminomethyl-2-ethyl-3 -methyl-7-methoxy chromone-HCl; 2-ethyl-3-methyl-7-methoxy-8-morpholinomethylchromone-HCl; 2,3-diethyl-7-methoxy-8-piperidinomethyl chromone-HCI; and 2,3-diethyl-7-methoxy-8-morpholinomethylchromone-HCI.
In order that the invention may be more clearly understood and readily carried into eifect with respect to Formula 1 the following non-limiting examples are given:
EXAMPLE I 8 Dimethylaminomethyl 7 Methoxy 3 Methyl 2- Phenyl Chr0m0ne-HCl A. mixture of 15.7 gr. of 8-chloromethyl-7-methoxy-3- methyl-Z-phenylchromone, 400 ml. of absolute ethanol and 15 ml. of an alcoholic solution of dimethylarnine 10% was heated in an autoclave for 5-8 hrs. at -100 C.
Removal of the solvent left a residue which was taken up in water and the separated base was taken up in chloro form. The chloroformic layer was washed 3 times with a saturated solution of NaCl, dried over anhydrous sodium sulphate, filtered and acidified with alcoholic hydrochloric acid in slight excess of the theoretical amount.
The removal of the solvent left a residue which on crystallizing from ethanol/ether gave gm. 9.87 of a white crystalline product having a melting point of 213214 C. (dec.).
Analysis calculated for C H O NClEiTective: Percent N, 3.90; percent Cl, 9.85. Calc.: Percent N, 3.90; percent Cl, 9.87.
EXAMPLE II 8 Diethylaminamethyl 7 Methoxy 3 Methyl 2- Phenylchromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-7-methoxy-3-methyl-2-phenylchromone and diethylamine in a molar ratio of 1:2.
The yield was 51% and a product was obtained having a melting point of l87-188 C.
Analysis for C H O NCl.-Efiec-tive: Percent N, 3.58; percent Cl, 9.10. Calc.: percent N, 3.61; percent CI, 9.14.
EXAMPLE III 7 Metlzoxy 3 Methyl 2 Plzenyl 8 Pipericlinomethyl Chromone-HCl The same procedure was followed as in Example I, starting with 8-chloromethyl-7-methoxy-3-methyl-2-phenyl chromone and piperidine in a molar ratio of 1:2.
The yield was of 71% and a product was obtained having a melting point of 217-218 C.
Analysis for C H O NCl.-Effective: Percent N, 3.52; percent Cl, 8.87. Ca1c.: Percent N, 3.50; percent Cl,
EXAMPLE 1V 7 Metlzoxy 3 Methyl 8 Morpholinometlzyl 2- phenyl Chromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-7-methoxy-3-methyl-2-phenyl chromone and morpholine in a molar ratio of 1:2.
The yield was 72% and a product was obtained having a melting point of 202-204 C.
Analysis for C H O NCl.-Elfective: Percent N, 3.48; percent Cl, 8.81. Calc.: Percent N, 3.49; Percent Cl, 8.82.
EXAMPLE V 8 Dimethylaminamethyl 3 Ethyl 7 Methoxy 2- phenyl Clzromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-3-ethyl-7-methoxy-2-phenyl chromone and dimethylamine in a molar ratio of 1:2.
The yield was of 31% and a product was obtained having a melting point of 208-209 C.
Analysis for C H O NCl.-Effective: Percent N, 3.75; percent Cl, 9.45. Cale: Percent N, 3.74; percent Cl, 9.48.
EXAMPLE VI 8-Dietl1ylaminomethyl-3-Ethyl-7-Met/10xy-Z-Pllenyl Chromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-3 ethyl-7-methoxy-2-phenyl chromone and diethylamine in a molar ratio of 1:2.
The yield was 36% and a product was obtained having a melting point of 205-206 C.
Analysis for C H O NCl.-Elfective: Percent N, 3.50;
percent Cl, 8.80. Ca1c.: Percent N, 3.49; percent Cl, 8.82. EXAMPLE VII 3 -Etl1yl-7-M etlzoxy-Z-Pl1enyl-S-Piperia'inometlzyl Clzromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-3-ethyl-7-methoxy-2-phenyl chromone and piperidine in a molar ratio of 1:2.
The yield was 43% and a product was obtained having a melting point of 226-227 C.
Analysis for C H O NCl.E1fective: Percent N, 3.36; percent Cl, 8.55. Calc.: Percent N, 3.38; percent Cl, 8.57.
EXAMPLE VIII EXAMPLE IX 2,3-Dimetl1yl-8-Dimethyl-Amin0methyl-7-Metlloxy C hromone-HCI The same procedure was followed as in Example I,
4 starting with 8-chloromethyl-2,3-dimethyl-7-methoxy chromone and dimethylamine.
The yield was 21% and a product was obtained having a melting point of -l92 C.
Analysis for C H O NCl.Elfective: Percent N, 4.68; percent Cl, 11.88. Calc.: Percent N, 4.70; percent Cl, 11.90.
EXAMPLE X 8-Dietl1ylamin0methyl-2,3-Dimethyl-7-Methoxy Chromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethy1-2,3-dimethyl-7-methoxy chromone and diethylamine.
The yield was 68% and a product was obtained having a melting point of 202-203 C.
Analysis for C H O NCl.Elfective: Percent N, 4.27; percent Cl, 10.85. Calc.: Percent N, 4.30; percent Cl, 10.89.
EXAMPLE XI 2,3 -Dimeth y [-7 -M etlz 0xy-8-Piper1' din omethyl Clzromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-2,3-dimethyl-7-methoxy chromone and piperidine.
The yield was 66% and a product was obtained having a melting point of 223-224 C.
Analysis for C H O NCl.Etfective: Percent N, 4.18; percent Cl, 10.47. Cale: Percent N, 4.15; percent Cl, 10.49.
EXAMPLE XII 2,3-Dimetlzyl-7-Meth0xy-8-M0rpholinomethyl Cln'omonc- HCl The same procedure was followed as in Example I, starting with 8-chloromethyl-2,3-dimethyl-7-methoxy chromone and morpholine.
The yield was 64% and a product was obtained having a melting point of 224-225" C.
Analysis for C H O NCl.Effective: Percent N, 4.10; percent Cl, 10.40. Calc.: Percent N, 4.12; percent C], 10.43.
EXAMPLE XIII 3 -El/2yl-2-M elhyl-7-M etlloxy-8-Piperidin0methyl Chromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-3-ethyl-2-methyl-7-methoxy chromone and piperidine.
The yield was 42% and a product was obtained having a melting point of -196 C.
Analysis for C H O NCl.Etfective: Percent N, 3.99; pgrggnt CI, 10.1. Calc.: Percent N, 3.98; percent CI,
EXAMPLE XIV 3-Etlzyl-2-Methyl-7-Merhoxy-S-Morpholinonzetlzyl Chromone-HCl The same procedure was followed as in Example I, starting with S-chloromethyl-3-ethyl-2-methyl-7-methoxy chromone and morpholine.
The yield was 53% and a product was obtained having a melting point of 208-209 C.
Analysis for C H O NCl.-Effective: Percent N, 3.94; p(e)r( ):ent Cl, 10.00. Calc.: Percent N, 3.96; percent CI, 1 2.
EXAMPLE XV 8-Diethylaminometlzyl-Z-Ethyl-3-Methyl-7-Melh0xy Chromone-HCI The same procedure was followed as in Example I,
starting with 8-chloromethyl-2-ethyl-3-methyl-7-methoxy chromone and diethylamine.
The yield was 44% and a product was obtained having a melting point of 185-186 C.
Analysis for C O O NCl.-Effective: Percent N, 4.13; percent Cl, 10.41. Calc.: Percent N, 4.12; percent Cl,
EXAMPLE XVI 2-Ethyl-3-Methyl-7-Meth0xy-8-M0rph0lin0methyl Chromone-HCI The same procedure was followed as in Example I, starting with 8-chloromethyl-2-ethyl-3-methyl-7-methoxy chromone and morpholine.
The yield was 46% and a product was obtained having a melting point of 214-215 C.
Analysis for C H O NCl.Effective: Percent N, 3.95; percent Cl, 10.1. Cale: Percent N, 3.96; percent Cl, 10.02.
EXAMPLE XVII 2,3-Diethyl-7-Methoxy-8-Piperidin0methyl Chromone-HCI The same procedure was followed as in Example I, starting with 8-chl0romethyl-2,3-diethyl-7-rnethoxy chromone and piperidine.
The yield was 44% and a product was obtained having a melting point of l84185 C.
Analysis for C I-I O NCl.Etfective: Percent N, 3.81; percent Cl, 9.70. Calc.: Percent N, 3.83; percent Cl, 9.69.
EXAMPLE XVIII 2,3-Dicthyl-7-Meth0xy-8-Morpholinomethyl Chromone- HCl The same procedure was followed as in Example I, starting with 8-chloromethyl-2,3-diethyl-7-methoxy chromone and morpholine.
The yield was 42% and a product was obtained having a melting point of l77-178 C.
Analysis for C H O NCl.Effective: Percent N, 3.75; percent Cl, 9.68. Calc.: Percent N, 3.81; percent Cl, 9.64.
In order to better illustrate the therapeutic value of the products of Formula 1, some data of the pharmacological tests are hereunder reported which show comparison to some of the better known medical products used as central stimulants, such as picrotoxin, metrazol and bemegride.
All these substances, when taken in high doses, cause tonic-clonic convulsions, evidence of the excitation of the central nervous system. Due to this reason, the DC (dose in mg./kg. which causes convulsions in 50% of the treated animals) can be considered an optimum reference for calculating the exciting power of the various drugs in relation to the metrazol taken as a standard.
In the class examined, there are drugs even more active than the picrotoxin, which was heretofore considered as the most active one among the stimulating substances of the central nervous system.
The value of the DL50, DC and RP (Relative Power referred to the metrazol expressed as a ratio between the DC thereof and the compound according to the present invention) are reported in the following table.
The analeptic activity of these products was tested to determine whether the DL of Nembutal, injected endoperitoneally into albino mice had an increased effect when treated with a single subcutaneous injection of the drugs under examination.
The values of this increase with reference to the compounds cited in Table I are reported in the following Table II.
It appears from the foregoing table that among the compounds of this invention, there are some capable of resisting the lethal effects of Nembutal in a greater meassure than the most active substances so far employed in this sense.
The breathing stimulating activity was tested on two compounds only of those illustrated above, namely on the compounds according to Examples XII and I, which are the most active compounds from the analeptic point of view.
The breathing stimulating activity was tested on nonnarcotized rabbits and on rabbits whose respiration was depressed by means of 10 mg./kg. of morphine.
These activities are reported in the following Table III.
In the above Table III the values are given of the therapeutic index (T.I.) and of the specific activity (S.A.), the latter in relation to metrazol and referred to the weight unit.
The last column gives the analeptic respiratory activity defined as the capacity of the drug in question to restore the morphine depressed breathing above the normal ventilation value.
The metrazol is not capable of restoring the depressed breathing up to the normal values and therefore bemegride was taken as a standard. 7
It appears clear from the foregoing that some of the compounds of this invention, and more particularly the compound according to Example I, are more active than some of the most widely known respiratory analeptics.
The compounds according to Examples X, XII, I and IX were tested in view of the chronic toxicity by giving them to albino mice growing up (10 males and 10 females) so that, for instance, said animals got pro die ca. A of the DL The treatment was continued for 50 days. The treated animals had, almost all, a weight increase greater than that of the control animals and an increase in red globules. No remarkable statistical differences between the weight averages of the various inner organs were found and no histologic lesions in said organs could be ascertained.
TABLE IV.-STRUCTURE AND PHARMACOLOGICAL ACTIVITY OF CNS STIMULANT ALKYLAMINOMETHYLCHROMONES II I WRu R9 \O/RIO CNS stimulatinz activity LDKB (Pcntylenetct- Rcs- Ana- From M01. razol 1) Effects upon pir- Inoloptic Sci- Exam- R R R Ru weight compared onarterial stimutroactivzuro ple No. pressure lant pisrn ity type action Mg./ Moles/ Weight Molar kg. kg. basis basis I C611 CH OCH; N(CH 359.24 4.8 13 14.8 30.54 NlL Nil c.t.
II C5115 CH OOH; N(C2H5)2 387.90 28 72 2.5 7.14 Nil Nll c,
III C511 OH; OCH; N 399.00 55 138 1.3 3.73 Nil Nil (I c.
IV C H OH OCH N O 401 87 85 212 0 8 2 42 Nl P t a 5 a '3 i osmvec..
V C H C211 OCHa N(CH3)2 373.87 54 3.5 9.52 Nil 0 Nil 0 c.
VI C 11 C211 OCH; N(C2H5)2---.- 01.92 60 149 1.2 3. 45 Nil 0.
VII C035 C211; OCH; N\- 413.93 550 1,329 0.1 0.39 Nil 0 Nil 0 6.1;.
VIII C H C H OCH N O 415 91 250 601 0 3 0 86 Nl t IX CH CH OCH; N(GH3)2 297.78 3.3 11 21.5 46 7'; Slightlyhy- Positive- (.t.
per cmsive.
X 0H: OH; 00111 M02115): 325.83 13 40 5.5 12.85 do Nil c.t.
XI CH CH OCH; N 337.84 17 50 4.2 10.28 (10 Nil 0.1;.
XII CH3 C 3 OCII3 N 0..... 339.81 17.4 50 4.1 10.08 Hypcrten- Positivec.t. sivc.
XIII CH 0 11 00113 N 351.87 50 142 1.4 3.62 Slightlyhy- Nil c.
. p ertenu slve. (IV CH C H OCH I '-\o 353 84 184 1 3 2 "9 V1 l\ l a z 5 a 1 I .1 l1 i c.
XV C211 CH OCHa N(C2H5)2 339.85 20 59 3.5 8.71 Hyperten- Nil c.t
sive. XVI C H CH OCH N 0 353 84 17 48 9 10 71 Nl N'l 15 a 5 3 3 o 1 l 0.
XVII C1115 C211 OOH; N 365.80 40 109 1.8 4.72 Nil Nil (Lt.
f XVIII C2115 C211 OCH: N 0..... 307.87 65 177 1.3 2. 00 Slightly hy- Positivec.
\... pertensivc.
The water-solubility was too low for intravenous administration. b The watcr-solubility was lower than 1% and therefore no proof of analeptic activity was performed. What is claimed is: in which R; and R are alkyl having less than 3 carbon 1. A compound of the formula: atoms,
u C m 65 N 11 and N 11 o l l C w CHQO FR:
| 0 R is a member selected from the group consisting of cmR-Hcl alkyl having less than 3 carbon atoms and phenyl and herein R 1s a member selected from the group con- R3 is alkyl having less than 3 carbon atoms. slstmg of 2. 8-dimethylaminomethyl 7 methoxy 3 methyl-2- R4 phenyl chromone-HCI. 3. 2,3-dimethyl 8 dimethyl-arninomethyl-7-methoxy- R5 5 chromone-HCI.
19 4. 2,3 dimethyl 7 methoxy-8-morpholinomethyl FOREIGN PATENTS chromowficl' 728,767 Great Britain Apr. 27, 1955 References Cited in the file of this patent OTHER REFERENCES UNITED STATES PATENTS 5 Da Re at 211.: Nature, vol. 184, pages 362 and 363;
3,046,275 Kohlstaedt et a1. July 24, 1962 August 1, 1959, Q IN 1.
Claims (1)
1. A COMPOUND OF THE FORMULA:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH7952259 | 1959-10-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3147258A true US3147258A (en) | 1964-09-01 |
Family
ID=4537246
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US155468A Expired - Lifetime US3147258A (en) | 1959-10-16 | 1961-11-28 | Amino chromones with central nervous system stimulating activity |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US3147258A (en) |
| BE (1) | BE595656A (en) |
| FR (1) | FR897M (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5143761A (en) * | 1974-08-13 | 1976-04-14 | Fuaruma Rehori Sa | Furabonjudotaino seizohoho |
| US6610738B2 (en) | 2000-09-21 | 2003-08-26 | Biogal Pharmaceutical Co., Ltd. | N-disubstituted carbamoyloxy flavones |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB728767A (en) * | 1951-10-12 | 1955-04-27 | Wander Ag Dr A | 2-substituted chromone compounds, and a method of making same |
| US3046275A (en) * | 1958-05-30 | 1962-07-24 | Chemiewerk Homburg Zweignieder | N-substituted 2-phenyl-7-aminoalkoxy chromones |
-
1960
- 1960-10-03 BE BE595656A patent/BE595656A/en unknown
-
1961
- 1961-01-10 FR FR849235A patent/FR897M/fr active Active
- 1961-11-28 US US155468A patent/US3147258A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB728767A (en) * | 1951-10-12 | 1955-04-27 | Wander Ag Dr A | 2-substituted chromone compounds, and a method of making same |
| US3046275A (en) * | 1958-05-30 | 1962-07-24 | Chemiewerk Homburg Zweignieder | N-substituted 2-phenyl-7-aminoalkoxy chromones |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5143761A (en) * | 1974-08-13 | 1976-04-14 | Fuaruma Rehori Sa | Furabonjudotaino seizohoho |
| US4079139A (en) * | 1974-08-13 | 1978-03-14 | Farmalepori | Flavone derivatives |
| US6610738B2 (en) | 2000-09-21 | 2003-08-26 | Biogal Pharmaceutical Co., Ltd. | N-disubstituted carbamoyloxy flavones |
Also Published As
| Publication number | Publication date |
|---|---|
| BE595656A (en) | 1961-02-01 |
| FR897M (en) | 1961-10-30 |
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